Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Effect of therapeutic hypothermia on surfactant proteins, anti-inflammatory and pro-fibrotic mediators

Journal of Perinatology volume 45, pages 1058–1063 (2025)Cite this article

Subjects

Abstract

Objectives

To study the effect of hypothermia on surfactant proteins, anti-inflammatory and pro-fibrotic mediators

Design

Prospective, pragmatic study enrolling asphyxiated neonates without lung injury. Surfactant proteins (SP), Club cell secretory protein (CC-10), tumor growth factor-β1 (TGF-β1), human fibroblast growth factor-2 (hFGF) and anti-inflammatory interleukins (IL) were measured in broncho-alveolar lavage fluids obtained before, during and after hypothermia.

Results

Twelve neonates were studied. SP-A, -B, -C, -D and CC-10 levels were similar before, during and after hypothermia. IL-10, IL-13, IL-14 were inconsistently detected only in five out of twelve patients and not in all timepoints; TGF-β1 was always undetectable. hFGF decreased during hypothermia (pre = 92 [52–193.6], during = 19.4 [0–42.6], post = 31.8 [0–83] ng/mL, p = 0.026) with levels before hypothermia being significantly higher than those obtained during and after the treatment (post hoc p = 0.025).

Conclusions

In cooled neonates without any lung disorder, hypothermia is associated with lower hFGF but not with any changes in surfactant proteins or anti-inflammatory molecules.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Hydrophilic surfactant proteins.
Fig. 2: Hydrophobic surfactant proteins.
Fig. 3: Illustrative anti-inflammatory and pro-fibrotic mediators.

Similar content being viewed by others

Data availability

The deidentified datasets are available from the corresponding author on reasonable request for research purposes and provided that all relevant regulations are respected.

References

  1. Pietrini D, Piastra M, Luca E, Mancino A, Conti G, Cavaliere F, et al. Neuroprotection and hypothermia in infants and children. Curr Drug Targets. 2012;13:925–35.

    Article  CAS  PubMed  Google Scholar 

  2. American Academy of Pediatrics. Committee on Fetus and Newborn, Hypothermia and neonatal encephalopathy. Pediatrics. 2014;133:1146–50. https://doi.org/10.1542/peds.2014-0899

    Article  Google Scholar 

  3. Hong SB, Koh Y, Lee IC, Kim MJ, Kim WS, Kim DS, et al. Induced hypothermia as a new approach to lung rest for the acutely injured lung. Crit Care Med. 2005;33:2049–55. https://doi.org/10.1097/01.CCM.0000178186.37167.53

    Article  PubMed  Google Scholar 

  4. Huang P-S, Tang G-J, Chen C-H, Kou YR. Whole-body moderate hypothermia confers protection from wood smoke-induced acute lung injury in rats: The therapeutic window. Crit Care Med. 2006;34:1160–7. https://doi.org/10.1097/01.CCM.0000207342.50559.0F

    Article  PubMed  Google Scholar 

  5. Ball MK, Hillman NH, Kallapur SG, Polglase GR, Jobe AH, Pillow JJ. Body temperature effects on lung injury in ventilated preterm lambs. Resuscitation. 2010;81:749–54. https://doi.org/10.1016/j.resuscitation.2009.12.007

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cruces P, Erranz B, Donoso A, Carvajal C, Salomón T, Torres MF, et al. Mild hypothermia increases pulmonary anti-inflammatory response during protective mechanical ventilation in a piglet model of acute lung injury. Pediatr Anesth. 2013;23:1069–77. https://doi.org/10.1111/pan.12209

    Article  Google Scholar 

  7. Angus SA, Henderson WR, Banoei MM, Molgat-Seon Y, Peters CM, Parmar HR, et al. Therapeutic hypothermia attenuates physiologic, histologic, and metabolomic markers of injury in a porcine model of acute respiratory distress syndrome. Physiol Rep. 2022;10:e15286. https://doi.org/10.14814/phy2.15286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Akyol O, Demirgan S, Şengelen A, Güneyli HC, Oran DS, Yıldırım F, et al. Mild Hypothermia via External Cooling Improves Lung Function and Alleviates Pulmonary Inflammatory Response and Damage in Two-Hit Rabbit Model of Acute Lung Injury. J Invest Surg. 2022;35:1472–83. https://doi.org/10.1080/08941939.2022.2064010

    Article  PubMed  Google Scholar 

  9. De Luca D, Shankar-Aguilera S, Autilio C, Raschetti R, Vedovelli L, Fitting C, et al. Surfactant-secreted phospholipase A 2 interplay and respiratory outcome in preterm neonates. Am J Physiol Lung Cell Mol Physiol. 2020;319:L95–104. https://doi.org/10.1152/ajplung.00462.2019

    Article  CAS  PubMed  Google Scholar 

  10. De Luca D, Vázquez-Sánchez S, Minucci A, Echaide M, Piastra M, Conti G, et al. Effect of whole-body hypothermia on inflammation and surfactant function in asphyxiated neonates. Eur Resp J. 2014;44:1708–10. https://doi.org/10.1183/09031936.00117714

    Article  Google Scholar 

  11. Autilio C, Shankar-Aguilera S, Minucci A, Touqui L, De Luca D. Effect of cooling on lung secretory phospholipase A2 activity in vitro, ex vivo, and in vivo. Am J Physiol Lung Cell Mol Physiol. 2019;316:L498–505. https://doi.org/10.1152/ajplung.00201.2018

    Article  CAS  PubMed  Google Scholar 

  12. Langman C, Orgeig S, Daniels CB. Alterations in composition and function of surfactant associated with torpor in Sminthopsis crassicaudata. Am J Physiol. 1996;271:R437–45. https://doi.org/10.1152/ajpregu.1996.271.2.R437

    Article  CAS  PubMed  Google Scholar 

  13. Suri LN, McCaig L, Picardi MV, Ospina OL, Veldhuizen RA, Staples JF, et al. Adaptation to low body temperature influences pulmonary surfactant composition thereby increasing fluidity while maintaining appropriately ordered membrane structure and surface activity. Biochim Biophys Acta. 2012;1818:1581–9. https://doi.org/10.1016/j.bbamem.2012.02.021

    Article  CAS  PubMed  Google Scholar 

  14. Autilio C, Echaide M, Cruz A, García-Mouton C, Hidalgo A, Da Silva E, et al. Molecular and biophysical mechanisms behind the enhancement of lung surfactant function during controlled therapeutic hypothermia. Sci Rep. 2021;11:728. https://doi.org/10.1038/s41598-020-79025-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Autilio C, Echaide M, Dell’Orto V, Perez-Gil J, De Luca D. Effect of Whole Body Hypothermia on Surfactant Function When Amniotic Fluid is Meconium Stained. Ther Hypothermia Temp Manag. 2020;10:186–89. https://doi.org/10.1089/ther.2017.0012

    Article  PubMed  Google Scholar 

  16. Autilio C, Echaide M, De Luca D, Perez-Gil J. Controlled hypothermia may improve surfactant function in asphyxiated neonates with or without meconium aspiration syndrome. PLoS One. 2018;13:e0192295. https://doi.org/10.1371/journal.pone.0192295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nespeca M, Giorgetti C, Nobile S, Ferrini I, Simonato M, Verlato G, et al. Does Whole-Body Hypothermia in Neonates with Hypoxic–Ischemic Encephalopathy Affect Surfactant Disaturated-Phosphatidylcholine Kinetics? PLoS One. 2016;11:e0153328. https://doi.org/10.1371/journal.pone.0153328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hayek AJ, White HD, Ghamande S, Spradley C, Arroliga AC. Is Therapeutic Hypothermia for Acute Respiratory Distress Syndrome the Future? J Intensive Care Med. 2017;32:460–4. https://doi.org/10.1177/0885066617701117

    Article  PubMed  Google Scholar 

  19. Pietrini D, Pennisi M, Vitale F, Pulitanò SM, Conti G, Mancino A, et al. Rescue hypothermia for refractory hypercapnia. Eur J Pediatr. 2012;171:1855–7. https://doi.org/10.1007/s00431-012-1769-6

    Article  PubMed  Google Scholar 

  20. Cruces P, Cores C, Casanova D, Pizarro F, Diaz F. Successful use of mild therapeutic hypothermia as compassionate treatment for severe refractory hypoxemia in COVID-19. J Crit Care. 2021;63:260–3. https://doi.org/10.1016/j.jcrc.2021.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Karnatovskaia LV, Festic E, Freeman WD, Lee AS. Effect of Therapeutic Hypothermia on Gas Exchange and Respiratory Mechanics: A Retrospective Cohort Study. Ther Hypothermia Temp Manag. 2014;4:88–95. https://doi.org/10.1089/ther.2014.0004

    Article  PubMed  Google Scholar 

  22. Slack DF, Corwin DS, Shah NG, Shanholtz CB, Verceles AC, Netzer G, et al. Pilot Feasibility Study of Therapeutic Hypothermia for Moderate to Severe Acute Respiratory Distress Syndrome. Crit Care Med. 2017;45:1152–9. https://doi.org/10.1097/CCM.0000000000002338

    Article  PubMed  PubMed Central  Google Scholar 

  23. Aslami H, Binnekade JM, Horn J, Huissoon S, Juffermans NP. The effect of induced hypothermia on respiratory parameters in mechanically ventilated patients. Resuscitation. 2010;81:1723–5. https://doi.org/10.1016/j.resuscitation.2010.09.006

    Article  PubMed  Google Scholar 

  24. De Luca D, Tingay DG, van Kaam A, Brunow de Carvalho W, Valverde E, Christoph Roehr C, et al. Hypothermia and Meconium Aspiration Syndrome: International Multicenter Retrospective Cohort Study. Am J Resp Crit Care Med. 2016;194:381–4. https://doi.org/10.1164/rccm.201602-0422LE

    Article  PubMed  Google Scholar 

  25. https://clinicaltrials.gov/study/NCT04545424 n.d. [Accessed on Sept 30, 2024]

  26. De Luca D, Capoluongo E, Rigo V. Study group on Secretory Phospholipase in Paediatrics (SSPP). Secretory phospholipase A2 pathway in various types of lung injury in neonates and infants: a multicentre translational study. BMC Pediatr. 2011;11:101. https://doi.org/10.1186/1471-2431-11-101.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361:1349–58.

    Article  CAS  PubMed  Google Scholar 

  28. De Luca D, Minucci A, Tripodi D, Piastra M, Pietrini D, Zuppi C, et al. Role of distinct phospholipases A2 and their modulators in meconium aspiration syndrome in human neonates. Intensive Care Med. 2011;37:1158–65. https://doi.org/10.1007/s00134-011-2243-z

    Article  CAS  PubMed  Google Scholar 

  29. de Blic J, Midulla F, Barbato A, Clement A, Dab I, Eber E, et al. On behalf of the ERS Task Force on bronchoalveolar lavage in children. European Respiratory Society. Bronchoalveolar lavage in children. Eur Resp J. 2000;15:217–31. https://doi.org/10.1183/09031936.00.15121700

    Article  Google Scholar 

  30. Dell’Orto V, Bourgeois-Nicolaos N, Rouard C, Romain O, Shankar-Aguilera S, Doucet-Populaire F, et al. Cell Count Analysis from Nonbronchoscopic Bronchoalveolar Lavage in Preterm Infants. J Pediatr. 2018;200:30–7.e2. https://doi.org/10.1016/j.jpeds.2018.04.074

    Article  PubMed  Google Scholar 

  31. McNeil JB, Shaver CM, Kerchberger VE, Russell DW, Grove BS, Warren MA, et al. Novel Method for Noninvasive Sampling of the Distal Airspace in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2018;197:1027–35. https://doi.org/10.1164/rccm.201707-1474OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Autilio C, Echaide M, Benachi A, Marfaing-Koka A, Capoluongo ED, Pérez-Gil J, et al. A Noninvasive Surfactant Adsorption Test Predicting the Need for Surfactant Therapy in Preterm Infants Treated with Continuous Positive Airway Pressure. J Pediatr. 2017;182:66–73.e1. https://doi.org/10.1016/j.jpeds.2016.11.057

  33. Autilio C, Echaide M, Benachi A, Marfaing-Koka A, Capoluongo ED, Pérez-Gil J, et al. Surfactant Injury in the Early Phase of Severe Meconium Aspiration Syndrome. Am J Respir Cell Mol Biol. 2020;63:327–37. https://doi.org/10.1165/rcmb.2019-0413OC

    Article  CAS  PubMed  Google Scholar 

  34. Griese M, Kirmeier HG, Liebisch G, Rauch D, Stückler F, Schmitz G, et al. ILD-BAL working group of the Kids-Lung-Register. Surfactant lipidomics in healthy children and childhood interstitial lung disease. PLoS One. 2015;10:e0117985. https://doi.org/10.1371/journal.pone.0117985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu M, Zhang J, Liu C. Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma. Exp Ther Med. 2018;15:539–47.

    CAS  PubMed  Google Scholar 

  36. Cook DB, McLucas BC, Montoya LA, Brotski CM, Das S, Miholits M, et al. Multiplexing protein and gene level measurements on a single Luminex platform. Methods. 2019;158:27–32. https://doi.org/10.1016/j.ymeth.2019.01.018

    Article  CAS  PubMed  Google Scholar 

  37. De Luca D, Lopez-Rodriguez E, Minucci A, Vendittelli F, Gentile L, Stival E, et al. Clinical and biological role of secretory phospholipase A2 in acute respiratory distress syndrome infants. Crit Care. 2013;17:R163. https://doi.org/10.1186/cc12842

    Article  PubMed  PubMed Central  Google Scholar 

  38. D’Aronco S, Simonato M, Vedovelli L, Baritussio A, Verlato G, Nobile S, et al. Surfactant protein B and A concentrations are increased in neonatal pneumonia. Pediatr Res. 2015;78:401–6.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Autilio C, Perez-Gil J. Understanding the principle biophysics concepts of pulmonary surfactant in health and disease. Arch Dis Child Fetal Neonatal Ed. 2019;104:F443–51.

    Article  PubMed  Google Scholar 

  40. Tokieda K, Ikegami M, Wert SE, Baatz JE, Zou Y, Whitsett JA. Surfactant Protein B Corrects Oxygen-Induced Pulmonary Dysfunction in Heterozygous Surfactant Protein B–Deficient Mice. Pediatr Res. 1999;46:708–14. https://doi.org/10.1203/00006450-199912000-00014

    Article  CAS  PubMed  Google Scholar 

  41. Chaby R, Garcia-Verdugo I, Espinassous Q, Augusto LA. Interactions between LPS and lung surfactant proteins. J Endotoxin Res. 2005;11:181–5. https://doi.org/10.1179/096805105X37358

    Article  CAS  PubMed  Google Scholar 

  42. Roldan N, Nyholm TKM, Slotte JP, Perez-Gil J, Garcia-Álvarez B. Effect of Lung Surfactant Protein SP-C and SP-C-Promoted Membrane Fragmentation on Cholesterol Dynamics. Biophys J. 2016;111:1703–13. https://doi.org/10.1016/j.bpj.2016.09.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Arbibe L, Koumanov K, Vial D, Rougeot C, Faure G, Havet N, et al. Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interaction. J Clin Invest. 1998;102:1152–60. https://doi.org/10.1172/JCI3236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Arroyo R, Khan MA, Echaide M, Perez-Gil J, Palaniyar N. SP-D attenuates LPS-induced formation of human neutrophil extracellular traps (NETs), protecting pulmonary surfactant inactivation by NETs. Commun Biol. 2019;2:470. https://doi.org/10.1038/s42003-019-0662-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Martinu T, Todd JL, Gelman AE, Guerra S, Palmer SM. Club Cell Secretory Protein in Lung Disease: Emerging Concepts and Potential Therapeutics. Annu Rev Med. 2023;74:427–41. https://doi.org/10.1146/annurev-med-042921-123443

    Article  CAS  PubMed  Google Scholar 

  46. Boilly B, Vercoutter-Edouart AS, Hondermarck H, Nurcombe V, Le Bourhis X. FGF signals for cell proliferation and migration through different pathways. Cytokine Growth Factor Rev. 2000;11:295–302.

    Article  CAS  PubMed  Google Scholar 

  47. Presta M, Andres G, Leali D, Dell’Era P, Ronca R. Inflammatory cells and chemokines sustain FGF2-induced angiogenesis. Eur Cytokine Netw. 2009;20:39–50. https://doi.org/10.1684/ecn.2009.0155

    Article  CAS  PubMed  Google Scholar 

  48. El Agha E, Seeger W, Bellusci S. Therapeutic and pathological roles of fibroblast growth factors in pulmonary diseases. Dev Dyn. 2017;246:235–44. https://doi.org/10.1002/dvdy.24468

    Article  CAS  PubMed  Google Scholar 

  49. Dargaville PA, South M, McDougall PN. Comparison of two methods of diagnostic lung lavage in ventilated infants with lung disease. Am J Respir Crit Care Med. 1999;160:771–7. https://doi.org/10.1164/ajrccm.160.3.9811048

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Faculty of Biology, and Research Institut Hospital 12 de Octubre, Complutense University, Madrid, Spain

    Chiara Autilio, Alejandro A. Alonso & Jesus Perez-Gil

  2. Centre de Recherche Saint-Antoine (CRSA)-INSERM U938, Sorbonne Université, Paris, France

    Lhousseine Touqui & Silvia Foligno

  3. Institut Pasteur, Mucoviscidose et Bronchopathies Chroniques, Département Santé Globale, Paris, France

    Lhousseine Touqui

  4. Division of Pediatrics and Neonatal Critical Care, “A. Béclère” Medical Center, Paris Saclay University Hospital, APHP, Paris, France

    Silvia Foligno & Daniele De Luca

  5. Division of Neonatology and Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Raquel Arroyo

  6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Paul S. Kingma

  7. Cincinnati Bronchopulmonary Dysplasia Center, The Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Paul S. Kingma

  8. Physiopathology and Therapeutic Innovation Unit-INSERM U999, Paris Saclay University, Paris, France

    Daniele De Luca

Authors
  1. Chiara Autilio
    View author publications

    Search author on:PubMed Google Scholar

  2. Lhousseine Touqui
    View author publications

    Search author on:PubMed Google Scholar

  3. Silvia Foligno
    View author publications

    Search author on:PubMed Google Scholar

  4. Raquel Arroyo
    View author publications

    Search author on:PubMed Google Scholar

  5. Paul S. Kingma
    View author publications

    Search author on:PubMed Google Scholar

  6. Alejandro A. Alonso
    View author publications

    Search author on:PubMed Google Scholar

  7. Jesus Perez-Gil
    View author publications

    Search author on:PubMed Google Scholar

  8. Daniele De Luca
    View author publications

    Search author on:PubMed Google Scholar

Contributions

CA: manuscript drafting, formal analysis, investigation, data curation. LT: laboratory assays, data interpretation, resources. SF: investigation, laboratory assays, resources. RA: investigation, laboratory assays, data curation, resources. PSK: investigation, data curation, resources. AAA: investigation, data curation, resources. JPG: investigation, validation, resources. DDL: study conception, manuscript drafting, formal analysis, methodology, resources. All authors critically revised the manuscript for important intellectual content and approved the final manuscript version to be published.

Corresponding author

Correspondence to Daniele De Luca.

Ethics declarations

Competing interests

PSK served as Chief Medical Officer from 2018-2021 for Airway Therapeutics inc. which is developing SPD as a human therapeutic agent; all his financial relationships with Airway Therapeutics inc. terminated in 2021. RA is currently an employee of Airway Therapeutics inc. JPG and DDL received research grants or consultancy fees from Airway Therapeutics inc. This company had no role whatsoever in design, preparation and conduction or review of the work, neither in the approval of the manuscript or decision to submit it for publication. The declared interests are all unrelated to the present work. The other authors have no conflicts of interest to disclose.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Autilio, C., Touqui, L., Foligno, S. et al. Effect of therapeutic hypothermia on surfactant proteins, anti-inflammatory and pro-fibrotic mediators. J Perinatol 45, 1058–1063 (2025). https://doi.org/10.1038/s41372-025-02285-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41372-025-02285-2

Search

Advanced search

Quick links